Routine Use of Acetaminophen

PEP Topic

Chronic Pain

Description

The routine addition of acetaminophen/paracetemol to a pain regimen of opioid analgesics in patients with chronic pain has commonly been used in practice, in order to improve overall pain control. The effects of this approach in pain management are beginning to be examined through research for effectiveness in managing chronic pain in patients with cancer.

Type of Resource/Evidence-Based Process:

PROCESS OF DEVELOPMENT: An interdisciplinary panel of experts in cancer pain management prepared these guidelines. When unavailable, recommendations were not made or were made on the recommendation of experts in that area.

Results Provided in the Reference:

Guidelines & Recommendations:

Make patient and family caregiver education about pain management a part of the treatment plan, and encourage patient and family caregivers to participate actively in pain management.

Collaborate with patients and family caregivers, taking costs and availability of treatment options into account when selecting pain management strategies. (Panel consensus)

Assessment

Perform a comprehensive pain assessment of all patients with cancer at each outpatient visit or hospital admission and use each patient’s self-report as the foundation for the assessment.

Include in the comprehensive pain assessment a detailed history to determine the presence of persistent and breakthrough pain and its effects on function; a psychosocial assessment; a physical examination; and a diagnostic evaluation of signs and symptoms associated with common cancer pain presentations and syndromes.

Cancer Pain Management

Develop a systematic approach to cancer pain management and teach patients and family caregivers how to use effective strategies to achieve optimal pain control.

Begin a bowel regimen to prevent constipation when the patient is started on an opioid analgesic.

Administer a long-acting opioid on an around-the-clock basis, along with an immediate-release opioid to be used on an as-needed basis, for breakthrough pain once the patient’s pain intensity and dose are stabilized.

Do not use meperidine in the management of chronic cancer pain.

Adjust opioid doses for each patient to achieve pain relief with an acceptable level of side effects.

Avoid intramuscular administration because it is painful and absorption is unreliable.

Use optimally titrated doses of opioids and maximal safe and tolerable doses of coanalgesics through other routes of administration before considering spinal analgesics. (Panel consensus)

Monitor for and prophylactically treat opioid-induced side effects.

Clarify myths and misconceptions about pain management, and reassure patients and family caregivers that cancer pain can be relieved and that addiction and tolerance are not problems associated with effective cancer pain management.

Use cognitive and behavioral strategies as part of a multimodal approach to cancer pain management, not as a replacement for analgesic medications.

Implement a formal process to evaluate and improve the quality of cancer pain management across all stages of the disease process and across all practice settings.

Evaluate the quality of cancer pain management at points of transition in the provision of services (e.g., from the hospital to the home) to ensure that optimal pain management is achieved and maintained.

Purpose & Patient Population:

The guidelines, which relate to the use of opioids to treat cancer pain, are the result of revision of previous European Palliative Care Research Collaborative guidelines.

Type of Resource/Evidence-Based Process:

In the development of the revised guidelines, collaborators assigned 22 topics to groups of reviewers, who completed the systematic review using a standardized method. The evidence profile of each relevant outcome was reviewed and became the basis of the final recommendations. The Scientific Advisory Board of the European Palliative Care Research Collaborative and the Board of Directors of the European Association for Palliative Care reviewed the recommendations. Upon revision, the recommendations were again distributed to the groups for comment and/or approval.

The data search completed in connection with the project was a systematic retrieval of randomized and nonrandomized trials and meta-analyses that

Involved adults with chronic cancer pain

Contained data on efficacy, side effects, and the treatments considered

Search keywords were terms relevant to each outcome. Outcomes related to the following: World Health Organization (WHO) step II opioids, WHO step III opioid of first choice, opioid titration, role of transdermal opioids, role of methadone, opioid switching, relative opioid analgesic potencies, alternative systemic routes of opioid administration, opioids for breakthrough pain, treatment of opioid-related emesis, treatment of opioid-related constipation, treatment of opioid-related central nervous system symptoms, use of opioids in patients with renal failure, role of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in addition to step III opioids, role of adjuvant drugs for neuropathic pain (antidepressants and anticonvulsants), and spinal route of opioid administration.

Studies were excluded if they dealt with the role of opioids in liver failure and the use of opioid combinations. (Data were of insufficient quality to support a recommendation regarding these topics.) Reviewers excluded a literature review regarding the treatment of opioid-related constipation; its content completely overlapped that of a Cochrane review. The role of ketamine was not included because resources to complete the work were unavailable.

Authors made 16 recommendations based on evidence profiles.

Phase of Care and Clinical Applications:

Patients were undergoing multiple phases of care.

The study has clinical applicability for palliative care, late effects and survivorship, and elder care.

Results Provided in the Reference:

Findings are submitted as a general framework to help clinicians make informed decisions regarding cancer pain management.

Guidelines & Recommendations:

Data reveal no differences regarding the use of morphine, oxycodone, and hydromorphone; any can be used as step III treatment.

Guidelines include a weak recommendation regarding oral opioids:

Immediate- and slow-release oral opioids can be used for dose titration.

Transdermal fentanyl and buprenorphine are step III alternatives, and some patients may prefer them.

Methadone can be used as a step III opioid but only by experienced providers, given its complex pharmacokinetic profile.

Guidelines include a weak recommendation regarding patients who are not getting adequate analgesia: These patients may benefit from opioid switching.

The subcutaneous route should be the first choice when alternate routes of administration are needed.

Breakthrough pain can be managed with oral, immediate-release opioids or buccal or intranasal fentanyl.

Guidelines include a weak recommendation about additions to step III opioids: Add NSAIDs or paracetamol to step III opioids. However, guidelines note that efficacy is not well documented.

Guidelines include a strong recommendation regarding neuropathic pain: Consider using amitriptyline or gabapentin for patients with neuropathic pain that is only partially responsive to opioids.

Guidelines include a weak recommendation regarding epidural and intrathecal opioids: Consider using an epidural or intrathecal opioid with a local anesthetic in cases of intractable pain or intolerable adverse effects.

Type of Resource/Evidence-Based Process:

These guidelines do not provide any information about search strategy or any specific evaluation of evidence. Notes state that most direct evidence is of low quality, but recommendations do result from unanimous consensus.

Guidelines & Recommendations:

The guidelines provide detailed recommendations regarding:

Screening and assessment

Management of pain in opioid-naive as well as opioid-tolerant patients

Limitations:

In general, opioids are first-line interventions. The NCCN guidelines suggest that antidepressants and anticonvulsants can be first-line treatments for adjuvant pain, although the recommendation for using them as such is still based on anecdotal experience or guidelines relating to patients who do not have cancer.

Nursing Implications:

The NCCN guidelines provide comprehensive algorithms for pain management, from screening to ongoing maintenance. The guidelines recommend considering a variety of nonpharmacologic interventions. Psychosocial support, including coping-skills training, is recommended, as is comprehensive patient and family education. The guidelines provide useful information and an overview of the full range of pain management. The work points to the ongoing need to consider multiple adjuvant and supportive interventions to achieve pain relief that works for the individual patient.

Study Purpose:

Intervention Characteristics/Basic Study Process:

Researchers assessed the difference in pain control in patients initially on a strong opioid in combination with paracetamol, over a four-day period, versus a strong opioid alone without paracetamol. Patients were asked to estimate their pain intensity at baseline, and then to stop paracetamol. If pain increased, patients were to take an extra dose of the opioid. If this was not effective, the paracetamol was restarted.

Sample Characteristics:

The study reported on a sample of 34 patients.

Median patient age was 68 years (range = 48–88 years).

The sample was 53% male and 47% female.

Prostate, pancreatic, breast, gynecologic, and bladder cancer were the most common patient diagnoses.

Setting:

Study Design:

The study used a prospective, descriptive, cohort design.

Measurement Instruments/Methods:

Numeric rating scale (0–10)

Interview

Results:

Only six patients (18%) wanted to continue with regular paracetamol, while 10 appreciated the opportunity to take paracetamol only as needed. There was no significant difference in average pain intensity with or without paracetamol. On day 4 at follow-up, 26% felt more pain, 6% felt less pain, and 68% reported no difference.

Conclusions:

The study supported the hypothesis that a fair number of patients on strong opioids do as well without paracetamol.

Limitations:

The study had a small sample, with less than 100 participants.

The study occurred over a short interval of time.

Nursing Implications:

The decision to utilize a combination of a strong opioid and paracetamol/acetaminophen should not necessarily be mandatory. It should be individualized for each patient, as there are patients who achieve pain control on the strong opioid alone, thus alleviating the need for additional medication in combination.

Cubero, D.I., & del Giglio, A. (2010). Early switching from morphine to methadone is not improved by acetaminophen in the analgesia of oncologic patients: A prospective, randomized, double-blind, placebo-controlled study. Supportive Care in Cancer, 18, 235–242.

Study Purpose:

To evaluate the efficacy of methadone as a substitute for morphine, and to investigate whether the addition of acetaminophen improves pain control in switching to methadone

Intervention Characteristics/Basic Study Process:

Patients using morphine for oncologic pain who were on a stable dose for at least one week were recruited. Patients were rapidly switched to oral methadone without a transition period and randomized to receive acetaminophen or placebo with methadone for seven days. The daily morphine dose was converted to methadone in ratios according to the total daily morphine dose. In case of additional pain, patients were instructed to use extra methadone no more than every two hours using a dose equal to 25% of the total daily dose. Use of coanalgesics such as anti-inflammatory drugs, antidepressants, and neuroleptics was allowed. Pain intensity was evaluated daily and recorded by patients in a diary along with all analgesic medications used. Patients were followed for seven days.

Sample Characteristics:

The study reported on 49 patients.

Median patient age was 58.5 years (range = 19–81 years).

The sample was 53% male and 47% female.

Various tumor types were cited, with the most frequent being colorectal, breast, and lung.

Eighty-eight percent of patients had non-neuropathic pain.

Median pain intensity at baseline was 5 in the acetaminophen group and 3.5 in the placebo group. Median morphine daily dose at baseline was 60 mg, with a range of 40–540 mg.

Setting:

Single site

Outpatient setting

Brazil

Study Design:

The study design was double-blind, randomized, placebo-controlled for use of acetaminophen, and open label for switch to methadone.

Measurement Instruments/Methods:

Numeric rating scale (0–10)

Faces pain rating scale

Four-point rating scale for side effects

European Organization for Research and Treatment Cancer Core Quality of Life questionnaire (EORTC QLQ-C30)

Results:

Of the original study sample, 16% ended participation early due to treatment failure with intense pain, somnolence, or vomiting. Most patients who completed the study had a significant improvement in pain by the faces (p = 0.05) and numeric (p = 0.03) rating scales. There were no differences between patients who did and did not receive acetaminophen.

Conclusions:

Study findings show that most patients can be switched from morphine to methadone with no transition period, with some improvement in side effects of constipation and xerostomia and adequate pain control. The addition of acetaminophen in this process was of no benefit.

Limitations:

The study had a small sample, with less than 100 participants.

No data were provided on total opioid consumption or use of rescue doses during the study.

The study period was very short, and even within this time frame, 16% experienced treatment failure with methadone.

No information was provided on actual use of adjuvant medications for pain control.

Nursing Implications:

This study shows that patients can be rapidly switched from morphine to methadone; however, this approach failed in 16% of patients. Methadone may be associated with less constipation and dry mouth, and may be a good pain control option for patients with these problems. Acetaminophen did not improve pain control with this switching process.

Study Purpose:

Intervention Characteristics/Basic Study Process:

Patients received usual medications plus 4 g paracetamol or placebo for five days each in random order. Primary outcome, effect on pain, was assessed using daily diaries, including a numeric rating scale ranging from 0 (no pain) to 10 (unbearable pain) and recording numbers of breakthrough analgesics. Patients also indicated in which part of the study their pain was better controlled.

Sample Characteristics:

The study reported on 22 patients who completed the study.

Mean patient age was 56.3 years (range = 28–79 years).

The sample was 55% male and 45% female.

Patients had a variety of cancer types.

Baseline pain score was greater than or equal to 2, and patients were using at least 200 mg daily morphine equivalents.

Setting:

Multisite

Both inpatient and community-based patients from Brisbane South Palliative Care Service and Mt. Olivet Palliative Care Service in Brisbane, Australia

Study Design:

The study used a randomized, double-blind, placebo-controlled, crossover design.

Measurement Instruments/Methods:

Numeric rating scale (0–10)

Patient-generated daily diary

Mini-Mental State Examination

Results:

There were no significant order or treatment-by-the-order interaction effects for any variable. There were no significant differences in pain when assessed with placebo compared with paracetamol. No change approached clinically significant levels, with a mean difference in rated pain of 0.16, and mean difference of 0.42 for a number of breakthrough medications. Fifteen patients were undecided whether paracetamol improved pain.

Conclusions:

Data from this study do not support the common practice of adding regular paracetamol (acetaminophen) daily to high-dose opioids to enhance pain control in the palliative setting.

Limitations:

The study had a small sample, with less than 30 participants.

Nursing Implications:

There is a growing body of evidence suggesting that some patients do not receive any additional benefit from adding paracetamol or acetaminophen to strong or high-dose opioids. Pain management interventions should be individualized. Unwarranted exposure to potential side effects/toxicities and costs should be avoided when possible by eliminating paracetamol or acetaminophen in those individuals in whom no benefit has been demonstrated.

Study Purpose:

To determine whether patients with bone cancer pain who were already administered opioids obtain clinically important pain control with regular oxycodone/paracetamol

Intervention Characteristics/Basic Study Process:

Patients received one to three placebo or oxycodone/paracetamol tablets four times per day for days 1–3, with the dosage titrated step by step based on pain assessment, up to 12 tablets per day, maximum. Patients recorded pain diary entries at baseline and on the study days. Immediate-release oral morphine was used to control breakthrough pain with 10% dose increments of the background continuous-release opioid, with no maximum (these were dispensed to the patient at the beginning of the study with specific instructions on administration). Patients remained on current background analgesic management, and additional analgesic drugs could be used, but not altered, during the study period.

Sample Characteristics:

A total of 246 patients began the trial, with 225 completing the three-day study.

Patient age range was 28–84 years.

Of the sample, 122 were male and 124 were female.

Patients had malignant solid tumors with bone metastasis confirmed via imaging, had bone-related pain rated as 4 or higher on an 11-point pain scale, and had received treatment with controlled-release morphine or transdermal fentanyl patches for one week or more. They had conscious mental status, the ability to take oral tablets, and were at least 18 years of age.

Patients were excluded from the study if they had received chemotherapy, radiation, or endocrine or monoamine oxidase inhibitors within the previous 30 days (or during the study), had history of alcohol abuse or severe hepatic disease, or had received nonsteroidal anti-inflammatory drugs or paracetamol combinations.

Setting:

Multisite

Home setting

Beijing, China

Phase of Care and Clinical Applications:

The study has clinical applicability for late effects and survivorship, and end-of-life and palliative care.

Study Design:

The study was a multicenter, randomized, double-blinded, placebo-controlled trial.

Results:

Prior to the study, 55.6% of the intervention group experienced breakthrough pain, while 50.8% of the placebo group did. After treatment, only 38% of the intervention group suffered breakthrough pain, while 58% of the placebo group did. The use of immediate-release morphine decreased from 50% to 27.8% in the intervention group while in the study, whereas the placebo group decreased from 46.7% pre to 43.3% in the same time frames.

Conclusions:

When oxycodone/paracetamol is added to intermediate- or high-dose continuous-release opioids, patients with bone cancer pain experienced greater relief of pain.

Limitations:

The authors cite that the study was conducted on only Chinese patients and point to the need to consider other ethnicities. There is no analysis based on overall analgesic regimens used, and no full description of these. Addition of this medication essentially increased the opioid dosing per day, so it is not clear whether this particular formulation was any more helpful than simple dosage increases.

Nursing Implications:

This study is applicable to patients with bone cancer pain who experience significant breakthrough pain while taking relatively high doses of a continuous-release opioid. It is not clear from this study how this particular formulation fits into an overall pain management regimen because it did provide higher dosage of opioid. Increasing opioid dosages may have had the same effect.

Study Purpose:

To examine the effectiveness of IV administration of paracetamol on the control of cancer pain and its possible contribution as reduction of opioid consumption

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive IV administration of saline (control) or 1 g of paracetamol on top of morphine.

Sample Characteristics:

The study reported on a sample of 43 patients.

Patient age range was 18–76 years.

Patients had chronic cancer pain without neuropathic origin; all had either somatic or visceral pain, but none had both types of pain.

Patients had a visual analog scale (VAS) score of greater than 4, a Pain Rating Index (PRI) score greater than 10, and an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 3.

Setting:

Single site

Outpatient setting

Pain clinic of Istanbul University

Study Design:

The study was double-blind, placebo-controlled, and randomized.

Measurement Instruments/Methods:

VAS

PRI

ECOG performance status

Statistical Package for Social Sciences (SPSS)

Two-way ANOVA

Chi-square test and Fisher’s exact test

Paired sample t test

Student t test

Mann-Whitney U test or Wilcoxon sign test

Results:

Both treatments resulted in improved VAS and PRI scores compared to baseline. However, groups did not differ in terms of VAS and PRI scores, morphine consumption, side-effect frequencies, laboratory values, ECOG stats, and patient satisfaction. The study failed to confirm any benefits of add-on treatment with IV administration of paracetamol.

Conclusions:

There was no benefit derived from adding IV paracetamol to morphine in an effort to enhance the effectiveness or contribute to reduction in opioid consumptions.

Limitations:

The study had a small sample.

Nursing Implications:

This study further supports the growing body of evidence that adding paracetamol to an opioid does not necessarily improve pain control or minimize the need for opioid. Pain management needs to be individualized. Further study in this area is warranted.

EXCLUSION CRITERIA: Not specified, but did exclude several studies in which patients were treated with a combination of hydrocodone or oxycodone and in which patients received transdermal fentanyl or morphine

Literature Evaluated:

TOTAL REFERENCES RETRIEVED = 3,703

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: No specific quality rating was applied–study limitations are described in the summary of findings of each study

Sample Characteristics:

FINAL NUMBER STUDIES INCLUDED = 9

TOTAL PATIENTS INCLUDED IN REVIEW = 175

SAMPLE RANGE ACROSS STUDIES: 22–172

KEY SAMPLE CHARACTERISTICS: Studies involved a mix of patients who did and did not also receive morphine for chronic pain management

Phase of Care and Clinical Applications:

APPLICATIONS: Palliative care

Results:

Five studies evaluated paracetamol. None of these demonstrated a meaningful benefit on pain intensity. Only one study reported a significant difference in pain intensity, but this difference was only 0.4 on a 10-point scale. Four studies evaluated NSAIDs. In all of these, patients were also on opioids. One of these compared two different NSAIDs. In the following three studies, use of NSAIDs appeared to have an opioid-sparing effect. Multiple study limitations were identified.

Conclusions:

No proof exists that paracetamol or NSAIDs should be used as the first step of the analgesic ladder. No evidence exists of benefit of paracetamol in combination with opioids. NSAIDs may have benefit in patients receiving opioids; however, further research is needed to confirm this.

Limitations:

Relatively few studies

Although one inclusion criterion was randomized, controlled trial, one study included was a non-randomized trial.

Nursing Implications:

Findings show that no evidence exists to show efficacy of the addition of acetaminophen to opioids for cancer pain management. Findings suggest that NSAIDs may provide additional benefit to patients on opioids for cancer pain; however, the evidence is limited, and studies done have not involved prolonged use. Nurses need to be aware of potential complications of long-term use of NSAIDs and educate patients regarding these. Selection of adjuvant pain management approaches needs to be made on an individual basis, and continued use needs to be determined on the basis of patient response.

Nabal, M., Librada, S., Redondo, M. J., Pigni, A., Brunelli, C., & Caraceni, A. (2012). The role of paracetamol and nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the control of pain in advanced cancer. A systematic review of the literature. Palliative Medicine, 26, 305–312.

Purpose:

To perform a systematic review of evidence of the efficacy and toxicity of nonsteroidal antiinflammatory drugs (NSAIDs) or paracetamol in addition to World Health Organization (WHO) step III opioid treatment for moderate to severe cancer pain in comparison to opioids alone

The type of study is systematic review.

Search Strategy:

Databases searched were MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials.
Search keywords were acetaminophen, paracetamol, neoplasm, pain, and NSAID.
Studies were included in the review if they were

A randomized controlled trial or a meta-analysis reporting on efficacy and/or side effects of NSAIDs or paracetamol in addition to opioids in comparison to opioids alone.

No specific exclusion criteria was identified.

Literature Evaluated:

A total of 803 references were retrieved.

After further review by the authors, 12 studies were included in the literature review.

Each study was evaluated in terms of content and quality using the Cochrane Handbook for Systematic Reviews of Interventions as the tool for appraisal.

Sample Characteristics:

A final number of 12 studies were included in the review.

The total number of patient cases included in the review was 396.

The article does not describe patient demographics or characteristics, including cancer diagnoses.

Phase of Care and Clinical Applications:

Patients were undergoing multiple phases of care.

The study has clinical applicability for palliative care.

Results:

Adjuvant use of NSAIDs has been demonstrated to provide an additive effect in either improving pain management or reducing opioid use. Paracetamol use did not demonstrate any significant improvement over opioid use alone.

Conclusions:

The articles reviewed provide weak support of the addition of NSAIDs to WHO step III opioids to improve analgesia and/or reduce opioid dose amount. The addition of paracetamol in combination with step III opioids cannot be supported by the current research review.

Limitations:

Several limitations were identified during the process of systematic review, including small sample, large losses to follow-up, no intention-to-treat analysis completed, short follow-up (one to five days), and evidence of sponsorship by industries (bias).

Nursing Implications:

This review adds to the body of evidence that routine use of acetaminophen to opioids for chronic pain management is not effective for pain reduction or reduction in opioid dosage needed for pain control. Acetaminophen does have potential negative effects with long-term or high-dose use, so this approach should not be implemented as a routine. A growing body of research is challenging the WHO ladder approach to pain management.